title: Global transitions of proteins explored by a multiscale hybrid methodology: application to adenylate kinase.
abstract: Efficient and accurate mapping of transition pathways is a challenging problem in allosteric proteins. We propose here a to our knowledge new methodology called collective molecular dynamics (coMD). coMD takes advantage of the collective modes of motions encoded by the fold, simultaneously evaluating the interactions and energetics via a full-atomic MD simulation protocol. The basic approach is to deform the structure collectively along the modes predicted by the anisotropic network model, upon selecting them via a Monte Carlo/Metropolis algorithm from among the complete pool of all accessible modes. Application to adenylate kinase, an allosteric enzyme composed of three domains, CORE, LID, and NMP, shows that both open-to-closed and closed-to-open transitions are readily sampled by coMD, with large-scale motions of the LID dominating. An energy-barrier crossing occurs during the NMP movements. The energy barrier originates from a switch between the salt bridges K136-D118 at the LID-CORE interface and K57-E170 and D33-R156 at the CORE-NMP and LID-NMP interfaces, respectively. Despite its simplicity and computing efficiency, coMD yields ensembles of transition pathways in close accord with detailed full atomic simulations, lending support to its utility as a multiscale hybrid method for efficiently exploring the allosteric transitions of multidomain or multimeric proteins.
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Mert
authors.initials: M
authors.lastname: Gur
authors.forename: Jeffry D
authors.initials: JD
authors.lastname: Madura
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D000263:Adenylate Kinase / Q000737:chemistry*; D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D016880:Anisotropy; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data
chemical_list: D000263:Adenylate Kinase